Phenolic resin microspheres, porous carbon microspheres, radioactive microspheres, and their manufacturing methods and applications

Abstract

This application discloses phenolic resin microspheres, porous carbon microspheres, radioactive microspheres, and their manufacturing methods and applications. The phenolic resin microspheres are obtained by mixing and reacting a phenolic compound, water, an aldehyde compound, an alkaline catalyst, and a dispersing medium, where the dispersing medium is selected from alkanes, cycloalkanes, silicone oils, heat-conducting oils, corn oil, peanut oil, olive oil, and industrial white oil, and no low-molecular-weight surfactants are added to the dispersing medium. The porous carbon microspheres prepared using the phenolic resin microspheres of this application can be used to load drugs or nuclides, and have the advantages of high loading rate, low washout rate, and high safety.

Description

[Technical Field]

[0001] This application also claims priority from Chinese patent application No. 2022115923907 filed on December 13, 2022, Chinese patent application No. 202211592412X filed on December 13, 2022, and Chinese patent application No. 2022116017505 filed on December 13, 2022. This application cites the above Chinese patent applications in their entirety.

[0002] <Technical field> The present application relates to the medical field, specifically to phenolic resin microspheres, porous carbon microspheres, radioactive microspheres and their manufacturing methods and applications. [Background technology]

[0003] Malignant tumors are diseases that pose a serious threat to human health, and currently there are various treatment methods, including chemotherapy, radiation therapy, interventional therapy, biological immunotherapy, etc. One of these therapies, the delivery of radioactive materials to cancer patients by positioning them, has already made great progress, in which the radioactive material is incorporated into small particles that can be directly implanted into solid tumors, and the α or β rays emitted from the radioactive elements are used to achieve local cell killing, reducing the impact of tumor cells on surrounding normal cells, and ensuring the therapeutic effect while maximizing safety.

[0004] In recent years, carbon microspheres have shown promising potential applications in adsorption, catalysis, drug delivery, energy storage, and other areas. Carbon materials are generally divided into three types: solid carbon microspheres, hollow carbon microspheres, and porous carbon microspheres. Among these, porous carbon microspheres have excellent properties such as a high specific surface area, high chemical stability, and high adsorption capacity, and are widely used in fields such as batteries and adsorption. Although some research has been conducted on the use of carbon microspheres as adsorption carriers to support drugs and even radioactive elements, there is little published information, and further research is needed.

[0005] At the same time, as an important precursor for producing porous carbon microspheres, phenolic microspheres are characterized by raw material stability, low cost, and high char yield. However, both commercially available products and phenolic microsphere raw materials reported in the literature generally have nanometer-sized particles or particle sizes exceeding 100 μm. Currently, phenolic microspheres are typically produced by mixing linear phenolic resin with a curing agent, followed by grinding, dispersion, and high-temperature curing. This process is cumbersome, and the resulting microspheres are often too large, often exceeding 100 μm in diameter. Conventional hydrothermal production methods also require high temperatures and pressures, long reaction times of 12 hours or more, and the limited solid content (typically 5% or less) is difficult to overcome, resulting in high production costs.

[0006] Therefore, it is necessary to provide phenolic resin microspheres, which can be used as an adsorption carrier by preparing porous carbon microspheres as precursors, and which can achieve high drug or radioactive element loading rates and low radioactive element loss rates, and a method for producing the same. Summary of the Invention [Problem to be solved by the invention]

[0007] The problem addressed by this application is to overcome the drawback of the prior art, which is the inability to simultaneously achieve high loading rates for carbon microspheres and low radioactive element loss rates, and to provide phenolic resin microspheres, porous carbon microspheres, and radiocarbon microspheres, as well as their manufacturing methods and applications. The radiocarbon microspheres described in this application have high loading rates for radionuclides and low rates of loss under static and vibration conditions, effectively improving the safety of radiocarbon microspheres during transport and storage, and enhancing the medical applicability of radiocarbon microspheres. At the same time, the phenolic resin microspheres described in this application have uniform particle size distribution and high yields. The manufacturing method for phenolic resin microspheres has good particle size control, fewer steps, low costs, and no need for curing agents or porogens, thereby reducing processing difficulties and production risks. The porous carbon microspheres manufactured using the phenolic resin microspheres described in this application have controllable particle size and are suitable for use in pharmaceutical applications (e.g., for loading metal elements), offering significant advantages of high loading rates, low loss rates, and high safety. [Means for solving the problem]

[0008] To achieve the above objectives, this application provides the following technical solutions: The first technical solution provided by this application is radiocarbon microspheres, which include porous carbon microspheres and a complex containing a radionuclide; wherein the porous carbon microspheres have a mesopore structure, the mesopores have an average pore size of 2 to 15 nm, and the radionuclide-containing complex is distributed within the mesopores; The specific surface area of ​​the porous carbon microspheres is 6 to 30 m 2 / g.

[0009] In the present application, the particle size of the porous carbon microspheres may be 1 to 150 μm, preferably 1 to 100 μm, and more preferably 10 to 60 μm (for example, 20 to 50 μm).

[0010] In the present application, the specific surface area of ​​the porous carbon microspheres is 10 to 30 m 2 / g, preferably 12 to 26m 2 / g, e.g., 10.01m 2 / g, 14.5m 2 / g, 22.3m 2 / g, 25.5m 2 / g.

[0011] In the present application, the average pore size of the mesopores may be 5 to 10 nm, preferably 6 to 9 nm, for example, 6.44 nm, 6.75 nm, 8.48 nm or 9.32 nm.

[0012] In the present application, in the complex containing the radionuclide, the radionuclide is 90 Y, 32 P, 192 Ir, 103 Pd, 89 Sr, 226 Ra, 131 I, 125 I, 188 Re, 186 Re, 153 Sm, 166 Ho, 111 In, 99m Tc, 192 Ir, 226 Ra, 177 Lu, 225 Ac, 212 Bi, 213 Bi and 223 Ra may be one or more selected from 90 It's Y.

[0013] In the present application, the ratio of the amount of the porous carbon microspheres to the amount of the radionuclide used is preferably 1:(0.033-0.233), more preferably 1:(0.067-0.233), even more preferably 1:(0.1-0.233), and still more preferably 1:(0.113-0.167). For example, when the mass of the porous carbon microspheres is 0.15 g, the mass of the radionuclide contained in the complex is 5-35 mg, or when the mass of the porous carbon microspheres is 0.15 g, the mass of the radionuclide contained in the complex is 10-35 mg, or when the mass of the porous carbon microspheres is 0.15 g, the mass of the radionuclide contained in the complex is 15-35 mg, or when the mass of the porous carbon microspheres is 0.15 g, the mass of the radionuclide contained in the complex is 17-25 mg.

[0014] In the present application, the complex containing the radionuclide is preferably obtained by reacting a solution containing the radionuclide with a solution containing a precipitant.

[0015] wherein the radionuclide is 90 Y, the solution containing the radionuclide is 90 Preferably it is a YCl3 solution.

[0016] In the solution containing the precipitant, the precipitant is preferably one or more of tartaric acid, EDTA, and sodium phosphate, more preferably tartaric acid, EDTA, or tartaric acid and sodium phosphate. The EDTA is preferably EDTA-2Na.

[0017] The second technical solution provided by this application is a method for producing radiocarbon microspheres, which includes the steps of Scheme 1 or Scheme 2 below: Method 1: Porous carbon microspheres are mixed with a solution containing radionuclides, and then a solution containing a precipitant is added to obtain a reaction solution, which is then reacted. Method 2: After mixing the porous carbon microspheres with a solution containing a precipitant, a solution containing a radionuclide is added to obtain a reaction solution, which is then reacted.

[0018] In the present application, in Method 1 and Method 2, the porous carbon microspheres have a mesopore structure, the average pore diameter of the mesopores is 2 to 15 nm, and the specific surface area of ​​the porous carbon microspheres is 6 to 30 m 2 / g.

[0019] In the present application, the concentration of the radionuclide in the reaction solution may be 0.02 to 0.15 mol / L, and preferably 0.05 to 0.12 mol / L.

[0020] In the present application, preferably, the molar concentration of the precipitant in the reaction solution is in excess of the molar concentration of the radionuclide in the reaction solution, more preferably 1.5 to 4 times, for example, the molar concentration of the precipitant is 2 times, 2.3 times, 2.5 times, 2.8 times, 3 times, 3.2 times, 3.5 times, or 3.8 times the molar concentration of the radionuclide.

[0021] In the present application, the solution containing the precipitant may be one or more of a tartaric acid solution, an EDTA solution, and a sodium phosphate solution, and is preferably a tartaric acid solution, an EDTA solution, or a mixed solution of a tartaric acid solution and a sodium phosphate solution. The EDTA solution is preferably an EDTA-2Na solution.

[0022] In the present application, after the reaction is completed, the complex containing the radionuclide can be distributed within the pores of the mesopores, and preferably, the complex containing the radionuclide is fixed within the pores of the mesopores.

[0023] In the present application, the reaction time may be 0.5 to 1.5 hours, for example, 0.6 hours, 0.7 hours, 0.8 hours, 0.9 hours, 1 hour, 1.1 hours, 1.2 hours, 1.3 hours, or 1.4 hours.

[0024] In the present application, after the reaction is completed, the method may further include a washing step, and the washing operation and conditions may be those conventional in the art, such as repeatedly washing with deionized water.

[0025] In the present application, the method for producing the porous carbon microspheres preferably includes a step of calcining and carbonizing resin microspheres (for example, phenolic resin microspheres or polystyrene microspheres).

[0026] The temperature for the calcination / carbonization is preferably 400 to 1000°C, and may be 400 to 800°C (e.g., 700 to 800°C). In the process of increasing the temperature from room temperature to the calcination temperature (e.g., 400 to 800°C), the temperature increase rate may be a rate common in the art, for example, 3°C / min to 10°C / min.

[0027] Here, the time for the calcination and carbonization may be 1 to 10 hours, preferably 3 to 6 hours, and more preferably 2 to 4 hours.

[0028] Here, the atmosphere for the baking and carbonization is preferably an Ar gas atmosphere.

[0029] In this application, according to the conventional practice in the art, after the carbonization is completed, the method for producing the porous carbon microspheres may further include the steps of washing, drying and sieving.

[0030] Here, the washing may be a conventional method used in the art, and preferably involves washing with diluted nitric acid (for example, 0.3 mol / L diluted nitric acid) and deionized water in that order.

[0031] Here, the drying may be conventional in the art, preferably vacuum drying or air drying box drying.

[0032] Here, the sieving may be performed by a method commonly used in the art, and preferably, the sieving is performed using a sieving machine.

[0033] In the present application, the method for producing the porous carbon microspheres preferably includes the following steps: The phenolic resin microspheres are placed in a tubular furnace and carbonized in an inert atmosphere. After carbonization, the microspheres are washed, dried and sieved to obtain the porous carbon microspheres.

[0034] The third technical solution provided by the present application is a method for producing phenolic resin microspheres, which comprises mixing and reacting a phenolic compound, water, an aldehyde compound, an alkaline catalyst and a dispersion medium to obtain the phenolic resin microspheres; Here, the dispersion medium is one or more selected from the group consisting of alkanes, cycloalkanes, silicone oils, thermally conductive oils, corn oil, peanut oil, olive oil, and industrial white oil, and no low molecular weight surfactant is added to the dispersion medium.

[0035] In the present application, the mixing may be conventional in the art, for example, first mixing the phenolic compound with deionized water, then adding a deionized water solution of alkaline catalyst, formaldehyde and a dispersing medium.

[0036] In the present application, the mixing may generally be performed under stirring conditions to achieve uniform mixing.

[0037] Here, the stirring may be conventional in the art, for example magnetic stirring.

[0038] The stirring speed is preferably 50 to 400 rpm / min, and may be 50 to 300 rpm / min or 70 to 400 rpm / min, or may be 100 to 300 rpm / min, 150 to 200 rpm / min, or 100 to 200 rpm / min.

[0039] When the dispersion medium is a hydrocarbon organic solvent (the above-mentioned alkanes and cycloalkanes), the stirring speed is preferably 50 to 300 rpm / min, more preferably 100 to 200 rpm / min.When the dispersion medium is an oil-based organic solvent (the above-mentioned silicone oils, heat-conductive oils, corn oil, peanut oil, olive oil, and industrial white oil), the stirring speed is preferably 70 to 400 rpm / min, more preferably 100 to 300 rpm / min, and even more preferably 150 to 200 rpm / min.

[0040] The stirring time is preferably 20 to 60 minutes, more preferably 30 to 40 minutes.

[0041] In the present application, the reaction temperature may be 50 to 100°C, and preferably 60 to 85°C.

[0042] The reaction time may be 24 to 72 hours, for example, 48 hours.

[0043] In this application, according to the conventional practice in the art, after the reaction is completed, the method for preparing the phenolic resin microspheres may further include steps of solid-liquid separation, washing and drying.

[0044] Here, the solid-liquid separation may be performed by any conventional method known in the art, preferably by filtration or rotary evaporation.

[0045] Here, the washing may be conventional in the art, preferably with absolute ethanol and deionized water.

[0046] Here, the drying may be conventional in the art, preferably vacuum drying or air drying box drying.

[0047] In the present application, the alkane may be any alkane known in the art, preferably one or more of n-pentane, n-hexane, n-heptane and n-octane, more preferably n-heptane.

[0048] In the present application, the cycloalkane may be any known in the art, with cyclohexane being preferred.

[0049] In the present application, the low molecular weight surfactant may be one known in the art, and generally refers to one or more surfactants having a molecular weight of less than 1000, such as Span surfactants (e.g., Span-80), Tween surfactants, sulfopropyl betaine surfactants (e.g., hexadecyl sulfopropyl betaine), sorbitan monooleate surfactants, sodium cocoyl propionate, bromohexadecyltrimethylamine (CTAB), dodecyl polyoxyethylene ether-9, and polyethylene glycol octylphenyl ether.

[0050] In the present application, the type of the alkaline catalyst may be any known in the art, and inorganic alkali is preferred, which may be one or more of ammonia water, metal hydroxides, carbonates, and bicarbonates, and is preferably one or more of metal hydroxides, carbonates, and bicarbonates.

[0051] Here, the metal hydroxide may be any known metal hydroxide in the art, and is preferably NaOH, KOH or Ca(OH)2.

[0052] Here, the carbonate may be any known in the art, and is preferably Na2CO3, K2CO3 or Cs2CO3.

[0053] Here, the bicarbonate may be any known in the art, and is preferably NaHCO3 or KHCO3.

[0054] The alkaline catalyst is preferably one or more of NaOH, KOH, Ca(OH)2, Na2CO3 and K2CO3, more preferably Na2CO3 or Ca(OH)2.

[0055] In the present application, the alkaline catalyst is generally provided in the form of its aqueous solution.

[0056] In the present application, the molar ratio of the phenolic compound to the alkaline catalyst may be 100:(0.001 to 0.1), preferably 100:(0.005 to 0.05), and more preferably 100:0.01.

[0057] In the present application, the phenolic compound may be any known compound in the art, and generally refers to a phenolic compound having or not having an electron-donating substituent on the benzene ring, preferably one or more of resorcinol, phenol, cresol, nonylphenol, aralkylphenol, cardanol, octylphenol, bisphenol A, and xylenol, more preferably resorcinol or phenol.

[0058] In the present application, the aldehyde compound may be any known compound in the art, and is preferably one or more selected from formaldehyde, acetaldehyde, and furfural, and more preferably formaldehyde.

[0059] In the present application, the aldehyde compound is generally provided as its aqueous solution, for example, a 37% aqueous formaldehyde solution.

[0060] In the present application, the molar ratio of the phenol compound to the aldehyde compound may be 1:(1 to 5), preferably 1:(2 to 4), and more preferably 1:3.

[0061] In the present application, the weight-to-volume ratio (w / v) of the phenolic compound to the water may be 1:(3 to 8) g / mL, preferably 1:(4.7 to 7) g / mL, and more preferably 1:(5 to 6.25) g / mL.

[0062] In the present application, the volume ratio of the water to the dispersion medium may be 1:(0.5 to 6), further may be 1:(0.75 to 6) or 1:(0.5 to 4), further may be 1:(1 to 5), more preferably 1:(2 to 4), and even more preferably 1:(2.4 to 3).

[0063] When the dispersion medium is a hydrocarbon organic solvent (the above-mentioned alkanes and cycloalkanes), the volume ratio of the water to the dispersion medium may be 1:(0.75 to 6), preferably 1:(1 to 5), more preferably 1:(2 to 4), and even more preferably 1:(2.4 to 3).When the dispersion medium is an oil-based organic solvent (the above-mentioned silicone oils, heat-conductive oils, corn oil, peanut oil, olive oil, and industrial white oil), the volume ratio of the water to the dispersion medium may be 1:(0.5 to 4), preferably 1:(1 to 3), for example, 1:1.67 or 1:2.

[0064] In the present application, the water may be deionized water as commonly used in the art. Unless otherwise specified, the "water" in the "weight-volume ratio of the phenolic compound to the water" and the "volume ratio of the water to the dispersion medium" includes the total volume of "water" when preparing the aqueous solution of the phenolic compound and when preparing the aqueous solution of the alkaline catalyst (when the alkaline catalyst is provided as an aqueous solution thereof).

[0065] In the present application, the method for producing the phenolic resin microspheres generally does not include the addition of a curing agent and / or a porogen, where the curing agent may be any known in the art, such as hexamethylenetetramine, melamine, etc., and the porogen may be any known in the art, such as toluene, DOP, stearyl alcohol, etc.

[0066] In the present application, the method for producing the phenolic microspheres may include the following steps: (1) A phenol compound, water, an alkaline catalyst, an aldehyde compound, and a dispersion medium are mixed under stirring to obtain a mixed liquid, and the dispersion medium is selected from an alkane and / or a cycloalkane. Preferably, the molar ratio of the phenolic compound to the alkaline catalyst is 100:(0.001 to 0.1), the volume ratio of the water to the dispersion medium is 1:(0.75 to 6), and the stirring speed is 50 to 300 rpm / min. (2) The mixture obtained in step (1) is placed in a reactor and reacted. Preferably, the reaction temperature is 50 to 100°C. (3) After the reaction in step (2) is completed, solid-liquid separation, washing and drying are carried out to obtain the phenolic resin microspheres.

[0067] In the present application, the method for producing the phenolic microspheres may include the following steps: (1) A phenol compound, an alkaline catalyst, water, an aldehyde compound, and a dispersing medium are mixed under stirring to obtain a mixed liquid, and the dispersing agent is one or more selected from silicone oil, heat-conducting oil, corn oil, peanut oil, olive oil, and industrial white oil. Preferably, the stirring speed is 70 to 400 rpm / min, the molar ratio of the phenolic compound to the alkaline catalyst is 100:(0.001 to 0.1), and the volume ratio of the water to the dispersion medium is 1:(0.5 to 4). (2) The mixture is placed in a reactor and allowed to react. (3) After the reaction in step (2) is completed, the phenolic resin microspheres are obtained by solid-liquid separation, washing, and drying.

[0068] The fourth technical solution provided by this application is phenolic resin microspheres, which are produced by the above-mentioned method for producing phenolic resin microspheres.

[0069] In the present application, the average particle size of the phenolic resin microspheres is preferably 20 to 40 μm or 30 to 50 μm.

[0070] When the dispersion medium is a hydrocarbon organic solvent (the above-mentioned alkane or cycloalkane), the average particle size of the phenolic resin microspheres is preferably 20 to 40 μm.

[0071] When the dispersion medium is an oily organic solvent (the silicone oil, heat conductive oil, corn oil, peanut oil, olive oil, and industrial white oil), the average particle size of the phenolic resin microspheres is preferably 30 to 50 μm.

[0072] The fifth technical solution provided by the present application is porous carbon microspheres, which have a mesopore structure, the average pore size of the mesopores is 2-15 nm, preferably 5-10 nm, and the specific surface area of ​​the porous carbon microspheres is 6-30 m 2 / g, preferably 10 to 30m 2 / g. Preferably, the particle size of the porous carbon microspheres is 10 to 60 μm, more preferably 20 to 50 μm. Preferably, the method for producing porous carbon microspheres includes a step of calcining and carbonizing resin microspheres (e.g., phenolic resin microspheres or polystyrene microspheres). Specific reaction conditions and parameters are as described above.

[0073] The sixth technical solution provided by this application is radiocarbon microspheres, which are produced by the above-mentioned production method.

[0074] The seventh technical solution provided by this application is the application of the aforementioned radiocarbon microspheres in the manufacture of drugs for treating tumors.

[0075] The eighth technical solution provided by this application is the application of the aforementioned radiocarbon microspheres in the production of radiopharmaceuticals.

[0076] The ninth technical solution provided by the present application is a method for treating tumors or cancer, specifically by administering a therapeutically effective amount of radiocarbon microspheres to a subject in need thereof. The radiocarbon microspheres are as described above.

[0077] As used herein, the term "therapeutically effective amount" refers to a safe dose sufficient to treat or alleviate the disease or symptoms. Typically, the therapeutically effective amount varies depending on the subject's medical history, age, medical condition, sex, and the severity and type of the subject's medical condition, as well as the administration of other active pharmaceutical ingredients, and those skilled in the art can determine the appropriate effective amount depending on the above circumstances.

[0078] In accordance with the common knowledge in the art, the above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present application.

[0079] All reagents and materials used in this application are commercially available.

[0080] The positive advancement effects of the present application are as follows: (1) By controlling the BET multipoint specific surface area and the average mesopore size of the produced porous carbon microspheres, the present application effectively improves the loading rate of the porous carbon microspheres against radioactive precipitates and reduces their static and vibrational washout rates, thereby improving the safety of radiocarbon microspheres during transportation and storage and enhancing the medical applicability of radiocarbon microspheres. (2) The method for producing phenolic resin microspheres in the present application involves mixing a reactive monomer, a catalyst, and a dispersing medium by stirring, followed by reaction to produce phenolic resin microspheres. Compared with the prior art process of prepolymerizing a reactive monomer under the action of a catalyst and then adding the prepolymer to a dispersing medium to form spheroids, the manufacturing process and post-treatment steps of the present application are simpler, the particle size is better controlled, and the microspheres are more suitable for interventional treatment such as hepatic artery radiotherapy embolization, with a uniform particle size distribution and a high yield. (3) The manufacturing method of phenolic resin microspheres in this application does not require the use of curing agents, porogens, etc., thereby reducing the use of unnecessary materials and easing the difficulty of processing. For example, hexamethylenetetramine is a hazardous chemical that is prone to explosion. The risk in the production process can be reduced by not using it. (4) The phenolic resin microspheres prepared according to the present invention are advantageous for producing porous carbon microspheres with controllable particle size, uniform particle size distribution, and high strength. The porous carbon microspheres are more suitable for loading nuclides, with a high loading rate and low flow-off rate, ensuring the safety of medication. [Brief explanation of the drawings]

[0081] [Figure 1] FIG. 1 is a particle size distribution diagram of the phenolic resin microspheres prepared in Example I-4. [Figure 2] 1 is a scanning electron microscope (SEM) photograph of the porous carbon material microspheres produced in Example 2-(1). [Figure 3] 1 is a scanning electron microscope (SEM) photograph of the porous carbon material microspheres produced in Example 2-(2). [Figure 4] FIG. 2 is a particle size distribution diagram of the phenolic resin microspheres prepared in Example II-2. [Figure 5] FIG. 1 is a particle size distribution diagram of porous carbon microspheres in Example 2-(3). [Figure 6] FIG. 1 is a graph showing the overall distribution curve of desorption pore volume versus pore size for porous carbon microspheres BJH in Example 2-(3). [Figure 7] 1 is a scanning electron microscope (SEM) photograph of porous carbon microspheres in Example 2-(4). [Figure 8] FIG. 1 is a particle size distribution diagram of porous carbon microspheres in Example 2-(4). [Figure 9] FIG. 1 is a graph showing the overall distribution curve of desorption pore volume versus pore size for porous carbon microspheres BJH in Example 2-(4). DETAILED DESCRIPTION OF THE INVENTION

[0082] The following examples illustrate the technical solutions of the present invention. Those skilled in the art should understand that the following examples are merely illustrative of the present invention and do not limit the scope of the present invention. Unless specific techniques or conditions are specified in the examples, they are carried out in accordance with the techniques or conditions described in the literature or in accordance with the product specifications. Unless the manufacturer is specified, the reagents or equipment used are all ordinary products available commercially. The formaldehyde used in the following examples is a 37% formaldehyde aqueous solution.

[0083] Terminology In this application, the terms "porous carbon material microspheres" and "porous carbon microspheres" have the same meaning, and the terms "radiocarbon microspheres" and "radiocarbon material microspheres" have the same meaning.

[0084] In the present application, the phrase "the complex containing the radionuclide is distributed within the pores of the mesopores" may be understood to mean that a part or all of the complex containing the radionuclide is distributed within the pores of the mesopores, or that the complex containing the radionuclide is distributed within the pores of the mesopores.

[0085] In the present invention, the terms "precipitate," "complex," and "complex precipitate" have the same meaning, and all refer to a precipitate in which a metal element (e.g., a radioactive element) is fixed, produced by reaction with a precipitant.

[0086] In the present invention, the term "precipitant" refers to a substance that can react with a radionuclide to produce particles with significantly reduced solubility, and can form a solid precipitate through various reaction types, such as complexation, chelating, association, salt formation, etc. Precipitants include tartaric acid, EDTA, sodium phosphate, 8-hydroxyquinoline, aromatic carboxylic acids, quinolones, flavonols, N,N'-bis(2-hydroxyphenyl)oxalic acid diamide, dibutyl methylphosphonate (DPMA), trifluoromethanesulfonic acid, 2,6-di-t-butyl-4-methylphenol, asparagine / glutamine, oxalate, thiocyanate, pyrophosphate ion, 5-fluorouracil, methacrylic acid / sorbic acid / salicylic acid. and 8-hydroxyquinoline, aromatic carboxylic acid and 1,10-o-phenanthroline / 4,4'-bipyridine, oxalic acid and o-phenanthroline, phenylalanine and o-phenanthroline, phosphate and serum protein, nicotinic acid and 8-hydroxyquinoline, isophthalic acid and acetylacetone, indole-3-propionic acid and o-phenanthroline, aspartic acid and o-phenanthroline, Schiff base and o-phenanthroline, etc.

[0087] The applicant first investigated the production of phenolic resin microspheres, with the objective of obtaining phenolic resin microspheres that are excellent in sphericity and have an average particle size that satisfies the required requirements in high yield.

[0088] Example 1 Production of Phenolic Resin Microspheres (Examples I-1 to I-15: Phenolic resin microspheres were produced using a hydrocarbon organic solvent as a dispersion medium. Examples II-1 to II-8: Phenolic resin microspheres were produced using an oily organic solvent as a dispersion medium.)

[0089] Examples I-1 to I-15 Phenolic resin microspheres were produced using a hydrocarbon organic solvent as a dispersion medium. The phenolic compound was mixed with deionized water and stirred magnetically to achieve uniform mixing. The deionized aqueous alkaline catalyst solution, formaldehyde, and dispersing medium were then added and stirred magnetically for 30 minutes to obtain a mixture. The mixture was transferred to a reactor and reacted at a constant temperature for 48 hours. The mixture was then washed with absolute ethanol and deionized water, vacuum dried at 60°C, and sieved to obtain phenolic resin microspheres. The specific process parameters and reaction results are shown in Table 1 below.

[0090] [Table 1] Note: The volume of deionized water in the above table is the total volume including deionized water in "When mixing phenolic compound and deionized water" and "Deionized aqueous solution of alkaline catalyst."

[0091] Comparative Example 1-4: Production of phenolic resin microspheres using a low molecular weight surfactant as a dispersion medium Other experimental conditions were the same as or almost the same as those in Example I. Phenolic resin microspheres were prepared by adding a low molecular weight surfactant to an alkane or cycloalkane dispersion medium or by directly using a low molecular weight surfactant dispersion medium. The specific process parameters and results are shown in Table 2.

[0092] [Table 2] Note: The volume of deionized water in the above table is the total volume including deionized water in "When mixing phenolic compound and deionized water" and "Deionized aqueous solution of alkaline catalyst."

[0093] Based on the above-mentioned investigation of the phenolic resin manufacturing method, the applicant discovered that the choice of dispersing medium has a significant impact on the spheroidization effect and particle size of phenolic resin microspheres. By selecting an alkane or cycloalkane as the dispersing medium and not adding a low-molecular-weight surfactant to the dispersing medium, phenolic resin microspheres with an average particle size controlled to 20 μm to 40 μm can be obtained in high yield. The addition of a low-molecular-weight surfactant significantly reduces the size of the microspheres, preventing them from reaching the desired particle size range. Without the addition of a dispersing agent, the manufactured product is less likely to be spherical.

[0094] Based on this, the inventors have attempted to increase the particle size of the microspheres by increasing the viscosity of the dispersion medium, for example, by using high-viscosity polyvinyl alcohol to form a dispersion system. However, this did not result in a significant increase in the overall size of the microspheres, and a large amount of blocking occurred in the reaction system, resulting in an extremely low yield of phenolic resin microspheres.

[0095] Examples II-1 to II-8: Production of phenolic resin microspheres using oily organic solvents as dispersion media The phenolic compound was mixed with deionized water and stirred uniformly under magnetic stirring. The deionized aqueous alkaline catalyst solution, formaldehyde, and dispersant were added and stirred magnetically at 70-400 rpm / min for 30 minutes to obtain a mixture. The mixture was transferred to a reactor and reacted at 60-100°C for 48 hours. The mixture was then washed with absolute ethanol and deionized water, vacuum dried at 60°C, and sieved to obtain phenolic resin microspheres. The specific reaction parameters are shown in Table 3.

[0096] [Table 3] Note: The volume of deionized water in the above table is the total volume including deionized water in "When mixing phenolic compound and deionized water" and "Deionized aqueous solution of alkaline catalyst."

[0097] Comparative Example 5: Phenolic resin microspheres were prepared by adding a surfactant to a dispersion medium of an oily organic solvent. Other experimental conditions were the same as or almost the same as those in Example II to prepare phenolic resin microspheres, and the specific reaction parameters are shown in Table 4.

[0098] [Table 4] Note: The volume of deionized water in the above table is the total volume including deionized water in "When mixing phenolic compound and deionized water" and "Deionized aqueous solution of alkaline catalyst."

[0099] The inventors investigated the use of oils alone as a dispersion system and found that the sphericity was good in all cases, the particle size of the microspheres increased, and the yield of microspheres with a diameter of 30 to 50 μm reached 65% to 85%. On the other hand, products manufactured by adding the low molecular weight surfactant CTAB to a silicone oil system became flaky and did not form spheres.

[0100] Example 2 Preparation of porous carbon microspheres After obtaining an ideal phenolic resin through the above-mentioned experimental studies, the applicant further investigated the production of porous carbon microspheres using the phenolic resin microspheres as a raw material.

[0101] Example 2-(1) Production of porous carbon material microspheres The phenolic resin microspheres produced in Example I-4 (the particle size distribution diagram is shown in Figure 1) were calcined at 700°C for 4 hours in an Ar atmosphere to produce porous carbon microspheres (the heating rate was 3°C / min). The porous carbon microspheres were washed twice with 0.3 mol / L diluted nitric acid and deionized water, dried, and sieved to obtain porous carbon microspheres (their scanning electron microscope image is shown in Figure 2). The BET multipoint specific surface area of ​​the porous carbon microspheres in Example 2-(1) was 10.01 m. 2 / g, and the average mesopore diameter was 9.32 nm.

[0102] Example 2-(2) Production of porous carbon material microspheres The phenolic resin microspheres produced in Example I-15 were calcined at 800°C for 4 hours in an Ar atmosphere to produce porous carbon microspheres (heating rate: 3°C / min). The porous carbon microspheres were washed twice with 0.3 mol / L diluted nitric acid and deionized water, dried, and sieved to obtain porous carbon microspheres (their scanning electron microscope image is shown in Figure 3). The BET multipoint specific surface area of ​​the porous carbon microspheres in Example 2-(2) was 22.32 m. 2 / g, and the average mesopore diameter was 6.75 nm.

[0103] Example 2-(3): Production of porous carbon material microspheres The phenolic resin microspheres prepared in Example II-2 (the particle size distribution diagram is shown in Figure 4) were calcined in an Ar atmosphere at 800°C for 4 hours to obtain porous carbon microspheres. The temperature was increased from room temperature to 800°C at a rate of 3°C / min. The particle size distribution of the porous carbon microspheres produced in Example 2-(3) is shown in FIG. 5, and the average particle size distribution was concentrated in the range of 25 to 38 μm. The BET multipoint specific surface area of ​​the porous carbon microspheres produced in Example 2-(3) was determined to be 14.5 m using a mesopore analyzer, model JW-BK112, manufactured by JWGB. 2 / g, the mesopore structure was clear, the mesopore size distribution was relatively uniform, and the average mesopore size was 6.44 nm. The desorption pore volume-pore size distribution curve of the porous carbon microspheres BJH in Example 2-(3) is shown in Figure 6.

[0104] Example 2-(4) Production of porous carbon material microspheres Preparation of porous carbon microspheres: Polystyrene microspheres (purchased from DuPont, USA, AmberChrom™ XT30) were calcined at 400°C for 4 hours in an Ar atmosphere (the temperature was raised from room temperature to 200°C at 10°C / min, then further raised to 400°C at 3°C / min, held for 240 minutes, and then cooled at a rate of 10°C / min) to prepare porous carbon microspheres. The SEM image of the porous carbon microspheres produced in Example 2-(4) is shown in Figure 7. The average particle size was concentrated in the range of 17 to 21 µm, as shown in Figure 8. The BET multipoint specific surface area of ​​the porous carbon microspheres produced in Example 2-(4) was determined to be 25.5 m using a mesopore analyzer, model JW-BK112, manufactured by JWGB. 2 / g, the mesopore structure was clear, the mesopore size distribution was relatively uniform, and the average mesopore size was 8.48 nm. The desorption pore volume-pore size distribution curve of the porous carbon microspheres BJH in Example 2-(4) is shown in Figure 9.

[0105] Example 3: Production of phenolic resin microspheres and porous carbon material microspheres (large-scale production) 640 g of resorcinol was mixed with 3 L of deionized water to homogenize the mixture, and then an aqueous sodium carbonate solution (62 g of sodium carbonate in 0.5 L of deionized water), 1.1 L of formaldehyde, and 10 L of n-heptane were added. The mixture was stirred magnetically at 200 rpm / min for 30 minutes to obtain a mixed solution. The mixed solution was transferred to a reactor and reacted at 60°C for 72 hours. After the reaction was completed, solid-liquid separation was performed to obtain phenolic resin microspheres, which were washed with n-heptane and ethanol, dried in a rotary evaporator, and then dried in a fan-air drying box to obtain phenolic resin microspheres (particle sizes distributed predominantly between 20 μm and 40 μm). The prepared phenolic resin microspheres were placed in a tubular furnace and carbonized under an argon gas atmosphere at 800°C for 4 hours to obtain porous carbon material microspheres, which were then washed with dilute nitric acid and purified water, dried in a blast drying box, and sieved to obtain porous carbon material microspheres. The particle size distribution was concentrated between 20μm and 40μm, and the yield was 76.2%.

[0106] Comparative Example 6: Production of phenolic resin microspheres and porous carbon material microspheres Carbon microspheres were produced using the method disclosed in Feng Zhong, Zhao Jianghong, Han Baixin et al., "Preparation of carbon microspheres by a phase inversion emulsification method without the use of emulsifiers and their electrochemical performance" [J]. New Carbon Materials, 2016, 31(6):600-608. The specific procedure is as follows: Heat-conducting oil and silicone oil were mixed in a mass ratio of 4:1 and preheated and stirred at 115°C for 1 hour. A certain amount of thermosetting phenolic resin and ethanol (mass ratio 1:4) were weighed and mixed uniformly with stirring. The mixture was gradually poured into the preheated oil mixture and stirred at 115°C for 2 hours (stirring speed 500 r / min). The mixture was then filtered, separated, washed, and dried to obtain phenolic resin microspheres. The obtained phenolic resin microspheres were carbonized at 800°C for 1 h in an Ar atmosphere to obtain porous carbon microspheres. The average particle size of the produced porous carbon microspheres was concentrated in the range of 10 to 20 μm, and the BET multipoint specific surface area was 540 m. 2 / g, and the average mesopore diameter was 0.89 nm.

[0107] Comparative Example 7: Production of phenolic resin microspheres and porous carbon material microspheres Phloroglucinol (1 eq), resorcinol (1 eq), and formaldehyde (1 eq) were dissolved in deionized water and stirred. The mixture was stirred for 5 min at a high rotation speed of 800 r / min, followed by 5 min at a low rotation speed of 100 r / min to prepare a precursor solution. The precursor solution was then added to industrial white oil containing 1% Span-80 (volume ratio of precursor solution to industrial white oil: 1:8), stirred until uniform, and then incubated in an oil bath at 25 °C for 12 h to produce a turbid solution. The turbid solution was separated by suction filtration and washed multiple times with dichloromethane to obtain a powdered solid. The powdered solid was carbonized at 850 °C for 5 h to obtain porous carbon microspheres. The particle size of the produced carbon spheres was concentrated between 1 and 10 μm, and the BET multipoint specific surface area was 930 m. 2 / g, and the average mesopore diameter was 18.56 nm. By using phenolic resin microspheres with an average particle size of 20-50 μm, the carbon microspheres produced have a specific surface area of ​​6-30 m 2 / g, preferably 10 to 30m 2The carbon microspheres had an average particle size controlled to 1 to 150 μm, preferably 10 to 60 μm, and an average pore size controlled to 2 to 15 nm. By controlling the BET multipoint specific surface area of ​​the porous carbon microspheres and the average pore size of the mesopores, it is expected that the loading rate of the porous carbon microspheres for radioactive precipitates can be improved and the rate of washout under static conditions and vibration can be reduced. As mentioned above, the applicant has a mean particle size of 10 to 60 μm and a specific surface area of ​​10 to 30 μm. 2 Porous carbon microspheres having a pore size of 5-10 nm and a pore size of 1000 nm / g are produced, and are expected to have a high loading rate and low washout rates under static and vibrational conditions when loaded with radioactive nuclides. The applicant has verified the effect of loading nuclides onto the carbon microspheres produced above.

[0108] Example of effect The porous carbon microspheres prepared in Example 2 and Comparative Examples 6 and 7 were immersed in 0.3 mol / L diluted nitric acid for 2 hours, then washed three times with deionized water, dried, and then used to support radioactive nuclide-containing complexes. 0.15 g of porous carbon microspheres are mixed with a precipitant solution and a YCl3 solution to obtain a reaction solution with a volume of 3 mL. The reaction can be carried out according to one of the following methods to load nuclides (the types of precipitants are listed in Tables 5 to 7). Method 1: First, add YCl3 solution and porous carbon microspheres until the YCl3 is fully absorbed into the mesopores of the porous carbon microspheres. Then, add the precipitant solution and react with the mesopores of the porous carbon microspheres to form a complex. Method 2: First, add the precipitant solution and the porous carbon microspheres so that the precipitant is fully absorbed into the mesopores of the porous carbon microspheres, and then add the YCl3 solution to react with the mesopores of the porous carbon microspheres to form a complex. The porous carbon microspheres were added to a solution containing a precipitant to obtain a mixture, which was then mixed uniformly and allowed to stand for 12 hours. After that, a YCl3 solution was added to the mixture and shaken on a shaker for 1 hour to ensure that the complex containing the radioactive nuclide was fully supported on the porous carbon microspheres. When the precipitant was tartaric acid and sodium phosphate, the porous carbon microspheres supported on the Y-tartaric acid complex were first added to the sodium phosphate solution, shaken on a shaker for 1 hour, washed, and dried to obtain the porous carbon microspheres supported on the Y-PO4 complex (EDTA was EDTA-2Na). After the reaction, the porous carbon microsphere solution was suction filtered three times with deionized water, and the final loading rate was measured. Half of the collected porous carbon microspheres were immersed in saline for 6 days, and the yttrium ion content in the solution was measured to calculate the static washout rate. The other half of the collected porous carbon microspheres was immersed in saline for 6 days and shaken every 12 hours for 30 minutes on a shaker. The yttrium ion content in the solution was measured and the vibration washout rate was calculated.

[0109] [Table 5]

[0110] [Table 6]

[0111] [Table 7]

[0112] As can be seen from Tables 5 to 7, (1) 90 Considering that the half-life of Y is 64.2 hours, it is usually used medically. 90 For product Y, the allowable interval between production and clinical application is generally no more than 5-6 days, so we set up indicators for static runoff rate and vibration runoff rate over a 6-day cycle to consider the quality and safety control level during normal and extreme storage periods. Furthermore, the high loading rate also had some impact on production costs and the complexity of post-treatment processes, so this was also considered.

[0113] The inventors surprisingly discovered that the loading rate and washout rate of the complex precipitant in porous carbon microspheres are affected by the mesopore size. The mesopore sizes of the porous carbon microspheres in Comparative Examples 6 and 7 were outside the scope of protection claimed in the present application. As can be seen from Tables 5 to 7, the loading rate in Comparative Example 6 was generally low, and the static washout rate and vibration washout rate in Comparative Example 6 were generally high. While not intending to be bound by any specific theory, based on the current experimental results, the inventors believe that the mesopore size of the porous carbon microspheres affects the loading and the robustness of the loading. When the mesopore size of porous carbon microspheres is small (e.g., less than 1 nm), the mesopore space is relatively limited, which limits the access of reactants to the mesopores. In addition, the ability to adsorb the complex precipitate formed outside the mesopores is insufficient, resulting in a low overall loading rate. When the mesopore size of porous carbon microspheres is large (e.g., greater than 15 nm), the mesopore space is large, and the amount of complex formed outside the mesopores that precipitates is sufficient to adsorb into the mesopores, resulting in a good loading rate. However, the mesopores have a relatively limited ability to interlock and fix the complex, which can take a long time to settle, and the washout rate, especially under vibration, is significantly high, failing to meet safety requirements. The inventors were the first to focus on the effect of mesopore size on the specific application of radioactive element loading, and by selecting carbon microspheres with a specific mesopore size range, they have effectively improved the level of control over the loading rate during product production and the washout rate during transportation and storage.

[0114] (2) The present inventors have found that porous carbon microspheres for loading metal elements must satisfy specific particle size and mesopore size requirements. However, to obtain porous carbon microspheres suitable for loading drugs or nuclides, specific particle size requirements must be met for the precursor organic microspheres. Using alkanes, cycloalkanes, and oils as dispersants, as shown in Examples I and II, without the addition of a low-molecular-weight surfactant, phenolic resin microspheres with particle sizes that meet the required size can be produced in high yields and with a good degree of sphericity. Furthermore, the porous carbon microspheres produced using these phenolic resin microspheres as precursors show little change in particle size, and the morphology of the microspheres after loading metal elements is well maintained, resulting in high strength.

Claims

1. a porous carbon microsphere and a complex containing a radionuclide; wherein the porous carbon microspheres have a mesopore structure, the mesopores have an average pore size of 2 to 15 nm, and the radionuclide-containing complex is distributed within the mesopores; The specific surface area of ​​the porous carbon microspheres is 6 to 30 m ２ / g of radioactive carbon microspheres.

2. 2. The radioactive carbon microspheres according to claim 1, wherein the particle diameter of the porous carbon microspheres is 10 to 60 μm.

3. The specific surface area of ​​the porous carbon microspheres is 10 to 30 m ２ 3. The radioactive carbon microspheres according to claim 1, wherein the average diameter of the mesopores is 5 to 10 nm.

4. In the complex containing the radionuclide, the radionuclide is ９０ Y. ３２ P. １９２ Ir, １０３ Pd, ８９ Sr, ２２６ Ra, １３１ I, １２５ I, １８８ Re, １８６ Re, １５３ Sm, １６６ Ho, １１１ In, ９９ｍ Tc, １９２ Ir, ２２６ Ra, １７７ Lu, ２２５ Ac, ２１２ Bi, ２１３ Bi and ２２３ 4. The radioactive carbon microspheres according to claim 1, wherein the radioactive carbon microspheres are at least one selected from Ra.

5. 5. The radioactive carbon microspheres according to claim 1, wherein the ratio of the amount of the porous carbon microspheres to the amount of the radioactive nuclide used is 1:(0.033-0.233).

6. The radioactive carbon microspheres according to at least one of claims 1 to 5, wherein the complex containing a radioactive nuclide is obtained by reacting a solution containing a radioactive nuclide with a solution containing a precipitant.

7. Radiocarbon microspheres according to at least one of claims 1 to 6, characterized in that the precipitating agent is at least one of tartaric acid, EDTA and sodium phosphate.

8. The method for producing the radiocarbon microspheres includes the steps of: (1) The concentration of the radioactive nuclide in the reaction solution is 0.02 to 0.15 mol / L; (2) The solution containing a precipitant is one or more of a tartaric acid solution, an EDTA solution, and a sodium phosphate solution; (3) The reaction time is 0.5 to 1.5 hours; (4) The radioactive carbon microspheres according to any one of the preceding claims, further comprising a washing step after the reaction is completed.

9. The radioactive carbon microspheres according to at least one of claims 1 to 8, characterized in that a method for producing the porous carbon microspheres includes a step of calcining phenolic resin microspheres or polystyrene microspheres to carbonize them.

10. the carbonization atmosphere is an inert atmosphere, The carbonization temperature is 400 to 1000°C, preferably 400 to 800°C; Radiocarbon microspheres according to at least one of claims 1 to 9, characterized in that the carbonization time is between 1 and 10 hours, preferably between 2 and 4 hours.

11. A method for producing phenolic resin microspheres, comprising: a method for producing the phenolic resin microspheres by mixing and reacting a phenolic compound, water, an aldehyde compound, an alkaline catalyst, and a dispersion medium; The method for producing phenolic resin microspheres is characterized in that the dispersion medium is one or more selected from the group consisting of alkanes, cycloalkanes, silicone oils, thermally conductive oils, corn oil, peanut oil, olive oil, and industrial white oil, and the dispersion medium is free of low-molecular surfactants.

12. a. the alkane is one or more of n-pentane, n-hexane, n-heptane, and n-octane; b) the cycloalkane is cyclohexane; c) the mixing step comprises first mixing the phenolic compound with deionized water, and then adding a deionized aqueous solution of an alkaline catalyst, formaldehyde, and a dispersion medium; d) The type of the alkaline catalyst is an inorganic alkali, and the inorganic alkali of the alkaline catalyst is one or more of ammonia water, metal hydroxide, carbonate, and hydrogen carbonate; e. the alkaline catalyst is provided in the form of an aqueous solution thereof; f) the molar ratio of the phenolic compound to the alkaline catalyst is 100:(0.001 to 0.1); g. The phenolic compound is one or more of resorcinol, phenol, cresol, nonylphenol, aralkylphenol, cardanol, octylphenol, bisphenol A, and xylenol; h) the aldehyde compound is one or more selected from the group consisting of formaldehyde, acetaldehyde, and furfural; i. The aldehyde compound is provided in the form of an aqueous solution thereof; j) the molar ratio of the phenol compound to the aldehyde compound is 1:(1 to 5); k. The weight-volume ratio of the phenolic compound to the water is 1:(3 to 8) g / mL; l. The volume ratio of the water to the dispersion medium is 1:(0.5 to 6); m. No curing agent and / or porogen is added in the process for producing the phenolic resin microspheres; and n. the mixing is performed under stirring conditions to achieve uniform mixing.

13. I. The metal hydroxide is NaOH, KOH or Ca(OH) ２ That is, The carbonate is Na ２ CO ３ , K. ２ CO ３ or Cs ２ CO ３ That is, Bicarbonate is NaHCO ３ or KHCO ３ That is, The alkaline catalyst is NaOH, KOH, Ca(OH) ２ , Na ２ CO ３ and K. ２ CO ３ One or more of the following: II. The molar ratio of the phenol compound to the alkali catalyst is 100:(0.005 to 0.05); III. The molar ratio of the phenol compound to the aldehyde compound is 1:(2 to 4); IV. The weight-volume ratio of the phenolic compound to the water is 1:(4.7 to 7) g / mL, and preferably, the weight-volume ratio of the phenolic compound to the water is 1:(5 to 6.25) g / mL; V. The volume ratio of the water to the dispersion medium is 1:(1-5), or preferably the volume ratio of the water to the dispersion medium is 1:(2-4); VI. The stirring speed is 50 to 400 rpm / min; VII. The reaction temperature is 50 to 100°C; VIII. The method for producing phenolic resin microspheres according to claim 11 or 12, wherein at least one of the conditions I to VIII is satisfied: VIII. The reaction time is 24 to 72 hours.

14. Application of radiocarbon microspheres according to at least one of claims 1 to 10 in the manufacture of drugs or radiopharmaceuticals for treating tumors.

15. It has a mesopore structure, the average pore diameter of the mesopores is 2 to 15 nm, and the specific surface area is 6 to 30 m ２ / g, and the particle size of the porous carbon microspheres is 10 to 60 μm.

Images